Cancer
Cancer is one of the leading causes of death worldwide, and cancer is difficult to diagnose and treat effectively. Accordingly, there is a need in the art for new compositions and methods for assessing and treating various cancers.
Cancer Stem Cells (CSCs)
Cancer stem cells (CSCs), which may also be referred to as tumor stem cells, are cancer cells that are operationally similar to normal stem cells and that typically have the ability to grow (or re-grow) a tumor. For example, like normal stem cells, CSCs typically possess the properties of self-renewal ability, extensive proliferation potential, and the potential to differentiate into multiple phenotypically different cell types. CSCs can potentially arise from, for example, mutation of a normal adult stem cell or from mutations that impart stem cell-like properties to another type of cell. Therefore, CSCs may or may not originate from their normal stem cell counterpart. However, regardless of whether or not the cell of origin of a CSC is in fact a true stem cell, the term CSC is used in the art on the basis of the cancer cell having properties that are similar to normal stem cells.
For example, recent studies have demonstrated that in many types of cancer, only a small subset of cancer cells within a tumor have the ability to proliferate extensively, to initiate the growth of new tumors (including metastatic growth), and to differentiate into the various different cell types that make up a typical, complex heterogeneous tumor. These cells are the CSCs, and these properties are typical of CSCs. Some CSCs have previously been isolated (e.g., from leukemia, as well as brain, breast, and lung cancers) and, when transplanted into an animal model (or even serially passaged into multiple animals), have been shown to be necessary and sufficient to initiate the growth of new tumors, whereas the vast majority of other cells within a tumor do not have the capability to initiate the growth of new tumors.
However, current cancer therapies (including, for example, chemotherapy and radiation therapy) generally attempt to non-discriminately kill proliferating cells, and potential therapeutic agents are commonly selected based on their ability to reduce tumor size. Furthermore, clinical trials of anti-cancer agents are commonly designed with the objective of demonstrating a reduction in tumor size. However, because cancer stem cells typically make up only a small proportion of a tumor, reduction in tumor size may not be indicative of any reduction in cancer stem cell populations, and therefore reduction in tumor size may not accurately reflect longer-term cancer prognosis. Because CSCs typically represent only a minor portion of a tumor and can be quiescent (non-proliferating), cancer therapies may primarily kill other cells that make up the majority of the tumor, thereby often leading to tumor shrinkage and possibly temporary cancer remission or other clinical improvement. However, because the CSCs have not been directly targeted and killed, CSCs may survive the cancer therapy and eventually initiate re-growth of the cancer. Thus, to permanently eradicate a cancer and to prevent metastasis, it would be desirable to specifically kill the CSCs. Similarly, to gain a more comprehensive diagnosis of a cancer, such as in predicting the reoccurrence of a cancer following treatment or the threat of metastasis, it would be desirable to specifically assess the CSCs.
Therefore, there is a need in the art to identify cancer stem cell markers (e.g., proteins expressed by cancer stem cells, and the encoding nucleic acid molecules), as well as agents (e.g., antibodies) that target these cancer stem cell markers, so that more effective cancer therapies and diagnostics can be implemented that specifically target the small population of tumor cells within a tumor that are cancer stem cells and which can be most harmful to a patient with regards to tumor growth, metastasis and initiation of new tumors, and re-growth of tumors following treatment.
For a further review of CSCs, see the following (each of these references is incorporated herein by reference): Fang et al., “A tumorigenic subpopulation with stem cell properties in melanomas”, Cancer Res. 2005 Oct. 15; 65(20):9328-37; Lee et al., “Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines”, Cancer Cell. 2006 May; 9(5):391-403; Nishizuka, “Profiling cancer stem cells using protein array technology”, Eur J. Cancer. 2006 June; 42(9):1273-1282; Reya et al., “Stem cells, cancer, and cancer stem cells”, Nature 2001 Nov. 1; 414(6859):105-11; Huff et al., “The paradox of response and survival in cancer therapeutics”, Blood 2006 Jan. 15; 107(2):431-4; Feinberg et al., “The epigenetic progenitor origin of human cancer”, Nat Rev Genet 2006 January; 7(1):21-33; Al-Hajj et al., “Therapeutic implications of cancer stem cells”, Curr Opin Genet Dev. 2004 February; 14(1):43-7; Soltysova et al., “Cancer stem cells”, Neoplasma 2005; 52(6):435-40; Wang et al., “Cancer stem cells: lessons from leukemia”, Trends Cell Biol. 2005 September; 15(9):494-501; Jordan, “Cancer stem cell biology: from leukemia to solid tumors”, Curr Opin Cell Biol. 2004 December; 16(6):708-12; Liu et al., “Adult stem cells and cancer stem cells: tie in or tear apart?”, J Cancer Res Clin Oncol. 2005 October; 131(10):631-8; Bjerkvig et al., “Opinion: the origin of the cancer stem cell: current controversies and new insights”, Nat Rev Cancer 2005 November; 5(11):899-904; Brabletz et al., “Opinion: migrating cancer stem cells—an integrated concept of malignant tumour progression”, Nat Rev Cancer 2005 September; 5(9):744-9; Jones et al., “Cancer stem cells: are we missing the target?”, J Natl Cancer Inst. 2004 Apr. 21; 96(8):583-5; Al-Hajj et al., “Self-renewal and solid tumor stem cells”, Oncogene 2004 Sep. 20; 23(43):7274-82; Kopper et al., “Tumor stem cells”, Pathol Oncol Res. 2004; 10(2):69-73; Cheng, “Cell cycle inhibitors in normal and tumor stem cells”, Oncogene 2004 Sep. 20; 23(43):7256-66; and U.S. Pat. No. 6,984,522 (“Isolation and Use of Solid Tumor Stem Cells”).